Fibroblast growth factor 20 (FGF-20) is a member of the fibroblast growth factor (FGF) family of secreted growth factors, a large group of growth factors found in organisms as diverse as C. elegans and H. sapiens (Itoh et al., 2004, Trends Genet 20:563-9). The FGF proteins identified to date belong to a family of signaling molecules that regulate growth and differentiation of a variety of cell types.
In vertebrates, there are twenty-two members of this family that differentially activate four distinct FGF receptors, playing distinct roles in the regulation of proliferation, migration, and differentiation during embryonic development (Ornitz et al., 2001, Genome Biol 2:REVIEWS3005). In adult tissues, FGF molecules function in injury and tissue repair, and many of them are overexpressed in cancer cell lines and can malignantly transform 3T3 cells when overexpressed (Ornitz et al., supra). In humans, three of the four genes for FGF receptors undergo mutational activation in different forms of cancer (Cappellen et al., 1999, Nat Genet 23:18-20; Richelda et al., 1997, Blood 90:4062-70; Xiao et al., 1998, Nat Genet 18:84-7).
Human FGF-20 was identified by three groups. One group discovered it based on its homology to Xenopus XFGF-20, which was first identified based on homology to Xenopus XFGF-9 (Kirikoshi et al., 2000, Biochem Biophys Res Commun 274:337-43; Koga et al., 1999, Biochem Biophys Res Commun 261:756-65). Another group identified FGF-20 using degenerate PCR primers in a search for novel FGFs and discovered the preferential expression of FGF-20 in the substantia nigra pars compacta of the brain (Ohmachi et al., 2000, Biochem Biophys Res Commun 277:355-60). This group also found that recombinant FGF-20 enhanced the survival of dopaminergic neurons, showing for the first time that a neurotrophic factor was preferentially expressed in brain tissue damaged by Parkinson's disease. See, U.S. Pat. No. 6,797,695. The third group identified FGF-20 by mining the human genome sequences. They showed that ectopic expression of FGF-20 promoted proliferation and transformed NIH-3T3 cells, and that three out of approximately sixty human cancer cell lines expressed abnormally high levels of FGF-20 (Jeffers et al., 2001, Cancer Res 61:3131-8). These attributes are not unique to FGF-20, since almost all FGFs tested show these properties.
Ectopic administration of recombinant FGF-20 has been shown to attenuate the development of inflammatory bowel disease in a rodent model, in part by promoting the proliferation and/or survival of intestinal epithelial cells (Jeffers et al., supra). Moreover, administration of recombinant FGF-20 prevents the formation of oral mucositis in hamsters receiving chemotherapy (Alvarez et al., 2003, Clin Cancer Res 9:3454-61).
FGF-20 has also been shown in gene expression microarray experiments to be a potential downstream target of β-catenin, a human oncogene that lies downstream in the Wnt signaling pathway (Chamorro et al., 2005, Embo J 24:73-84). FGF-20 has also been shown to be a potential target for β-catenin in rat epithelial cells transformed by mutant β-catenin as well as in primary human ovarian endometrioid adenocarcinomas with Wnt pathway defects (Wu et al., 2001, Cancer Res 61:8247-55). Knockdown of FGF-20 by RNA interference (RNAi) in rat epithelial cells blocks the ability of β-catenin to induce anchorage-independent growth, an in vitro correlate of tumorigenicity (Chamorro et al., supra). However, in these studies, FGF-20 was not always upregulated in tumors with Wnt/β-catenin activation.
Comparative genomics analyses on FGF-20 orthologs have shown that FGF-20 is well conserved among vertebrates. For example, the zebrafish FGF-20 gene shows 76.9%, 76.4%, 76.0% and 75.5% amino-acid identity with human, Xenopus, rat and mouse FGF-20, respectively (Katoh et al., 2005, Oncol Rep. 14:287-90). Human FGF-20 links to the EF hand domain family, member A2 (EFHA2) gene in a head-to-head manner with an interval of about 25 kb. EFHA2 is a gene of unknown biological function. The FGF20-EFHA2 locus at human chromosome 8p22 and the FGF9-EFHA1 locus at human chromosome 13q12.11 are paralogous regions (paralogons) within the human genome (Katoh et al., supra)